This project is directed at developing an in-depth understanding of how retroviruses induce immunodeficiency and how this disorder can be prevented and treated. Studies are based on analyses of mice infected with a unique set of retroviruses, designated LP-BM5 murine leukemia viruses (MuLV), that develop a disease, termed mouse AIDS (MAIDS), with many similarities to HIV-induced disease in humans. The etiologic virus in this mixture is a defective MuLV (BM5def) which encodes a gag protein that appears to act as a superantigen. Mice infected with the viruses develop both humoral and cellular immune responses to BMdef. In A/J mice, a strain resistant to development of MAIDS, an anti-BM5def response by CD8+ T cells effects clearance of the virus, thus preventing disease. CD8+ CTL are also responsible for restricting the spread of ecotropic helper virus in mice of this strain. CD8+ responses to BM5def-encoded antigens can also be induced in MAIDS-sensitive mice, but appear to be inadequate to control virus spread. In other studies, cyclosporin A, a drug that limits CD4+ T cell cytokine production was active in preventing rapid progression of MAIDS. By combining cyclosporin with the anti-viral drug ziduvodine (AZT), an additive effect could be seen on lympho-proliferation. The large proportion of CD4+ cells proliferating in mice sensitive to MAIDS can be ascribed to the high frequencies of BM5def-responsive cells found among T cells expressing Vbeta5.1, 5.2, 8.2, 11, 12, 14 and 17a. Using mice bearing some of these T cell receptor specificities as transgenes, it will be possible to have large numbers of cells responsive to the MAIDS superantigen for analyses of the biochemical events responsible for the state of anergy that characterizes the late stages of MAIDS. In mice with long term disease, splenic T cells are nonresponsive, as measured by proliferation, to stimulation through the T cell receptor or through CD28. They also fail to respond following stimulation by PMA and ionomycin. This contrasts with a relative conservation of function by lymph node cells from the same mice.